The present invention concerns certain 2-phenethylpiperidines bearing either urea, thiourea, or amidine substituents in the ortho-position of the phenethylamine phenyl ring. This invention particularly relates to these compounds and their acid addition salts with respect to their antiarrhythmic properties.
A related series of antiarrhythmic 2-phenethylpiperidines bearing amide substituents in the ortho-position of the phenyl ring has been previously described. One embodiment of that series is an antiarrhythmic agent known as encainide which is currently undergoing clinical evaluation. Encainide hydrochloride is also referred to in the literture as MJ 9067 (USAN and the USP Dictionary of Drug Names 1980, p. 122, United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, Library of Congress Catalog Card No. 72-88571). Encainide has the following structural formula (1) ##STR1##
The following publications describe the chemical synthesis of encainide and closely related compounds and its antiarrhythmic properties in animals.
Dykstra, S. J., et al., J. Med. Chem., 16, 1015-1020 (1973).
S. J. Dykstra and J. L. Minielli, U.S. Pat. No. 3,931,195 patented Jan. 6, 1976; U.S. Pat. No. 4,000,143 patented Dec. 28, 1978; U.S. Pat. No. 4,064,254 patented Dec. 20, 1977.
Byrne, J. E., et al., J. Pharmacology and Experimental Therapeutics, 200, 147-154 (1977).
Prior art related to the present invention is described in E. R. Squibb & Sons, Inc., British Specification Nos. 1,290,365 and 1,290,366 (divisionals) published Sept. 27, 1972.
These two British patents disclose substituted ureas with antiarrhythmic properties having the generic formula (2) ##STR2## Although some of the urea compounds of the instant invention read on this generic formula, none of them is exemplified or shown as a specific embodiment in the British specifications.
A related reference is Krapcho, J., U.S. Pat. No. 3,852,339 issued Dec. 3, 1974. This patent discloses aminoalkoxyphenylurea derivatives with antiarrhythmic properties. These compounds have general structure (3) ##STR3## The incorporation of an ether oxygen atom in the alkyl chain of these compounds additionally distinguishes them from the instant urea compounds.
The piperidino ureas and thioureas (4) ##STR4## described in Archibald, J. L. and Jackson, J. L., U.S. Pat. No. 4,073,790 issued Feb. 14, 1978 are disclosed as having antihypertensive utility. They bear some of the same structural elements as the presently claimed substances, but are otherwise dissimilar.
The structures of encainide and a number of analogs thereof, described in the foregoing publications and patents, differ from the compounds comprising the instant invention in the nature of the phenethyl moiety's ortho substituent. Encainide and its related analogs have o-amido functions whereas the subject compounds of this application have o-urea, -thiourea, and -amidine substituents thereon.